SUMMARY The accumulation of somatic DNA mutations over time is a hallmark of aging in many tissues. However, the causal role of somatic mutations in age-associated disorders other than cancer is a matter of debate, and remains unexplored in the setting of cardiovascular disease (CVD), the leading cause of death in elderly individuals. Recent large exome sequencing studies in humans have shown that aging is inevitably associated with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive growth advantage to the mutant cell and thus allow its clonal expansion (clonal hematopoiesis). Unexpectedly, these somatic mutations were associated with a higher rate of cardiovascular-related deaths, suggesting a previously unrecognized link between somatic mutations in bone marrow-derived cells and CVD. Recently, we reported that pre-cancerous driver mutations in Tet2 that occur in hematopoietic stem cells may be causally linked to cardiovascular disease. However, whether there is a causal connection between other clonal hematopoiesis genes and CVD remains unclear and the potential underlying mechanisms are completely unknown; and this is the scientific premise of the proposed research. Here, we will use a lentivirus/CRISPR gene editing approach to manipulate other hematopoietic stem cell driver genes and assess their impacts in a multi-faceted model of cardio-metabolic disease.